Asian Journal of Andrology (2015) 17, 26–31 © 2015 AJA, SIMM & SJTU. All rights reserved 1008-682X www.asiaandro.com; www.ajandrology.com
Open Access
Male Endocrinology
INVITED REVIEW
Testosterone deficiency and cardiovascular mortality Abraham Morgentaler New concerns have been raised regarding cardiovascular (CV) risks with testosterone (T) therapy (TTh). These concerns are based primarily on two widely reported retrospective studies. However, methodological flaws and data errors invalidate both studies as credible evidence of risk. One showed reduced adverse events by half in T‑treated men but reversed this result using an unproven statistical approach. The authors subsequently acknowledged serious data errors including nearly 10% contamination of the dataset by women. The second study mistakenly used the rate of T prescriptions written by healthcare providers to men with recent myocardial infarction (MI) as a proxy for the naturally occurring rate of MI. Numerous studies suggest T is beneficial, including decreased mortality in association with TTh, reduced MI rate with TTh in men with the greatest MI risk prognosis, and reduced CV and overall mortality with higher serum levels of endogenous T. Randomized controlled trials have demonstrated benefits of TTh in men with coronary artery disease and congestive heart failure. Improvement in CV risk factors such as fat mass and glycemic control have been repeatedly demonstrated in T‑deficient men treated with T. The current evidence does not support the belief that TTh is associated with increased CV risk or CV mortality. On the contrary, a wealth of evidence accumulated over several decades suggests that low serum T levels are associated with increased risk and that higher endogenous T, as well as TTh itself, appear to be beneficial for CV mortality and risk. Asian Journal of Andrology (2015) 17, 26–31; doi: 10.4103/1008-682X.143248; published online: 18 November 2014 Keywords: cardiovascular; mortality; myocardial infarction; risk; stroke; testosterone
INTRODUCTION As the use of testosterone (T) therapy (TTh) has increased substantially over the last decade,1 there has been increased attention paid to the health consequences of testosterone deficiency (TD), as well as to the potential risks of its treatment. One of the key topics in this area is the relationship of TD to cardiovascular (CV) health, particularly CV mortality. The purpose of this article is to review the literature regarding this issue. In the 1970s and 1980s, as epidemiologic studies demonstrated that men suffered from higher rates of myocardial infarctions (MIs) and CV deaths than women for every decade of life, it was speculated that T played a significant role in CV disease, as a clear difference between men and women was the presence of substantial serum concentrations of T in men.2 However, this belief largely disappeared once studies investigating the relationship of T and CV disease began to show that atherosclerosis in men was more prevalent in men with low T concentrations, and men with higher T concentrations appeared to be protected.3 Over the last 20 years, the major focus of potential risks of TTh has been its impact on prostate cancer (PCa). Whereas it had been long assumed that raising serum T would increase the risk of PCa and would cause any existing foci of PCa to grow rapidly,4 data accumulated over nearly 20 years failed to support this belief.5 Curiously, just as concerns regarding PCa have declined, we are once again faced with concerns regarding CV risk. As reviewed in greater detail below, a sizable number of observational studies have investigated the association of serum T concentrations and mortality, and more specifically, CV mortality, in Men’s Health Boston, Harvard Medical School, Boston, MA, USA. Correspondence: Dr. A Morgentaler ([email protected]) Received: 05 July 2014; Accepted: 22 July 2014
men. The majority of those studies have shown a significant association between lower serum T concentrations and mortality, with a smaller number showing no association. None of these observational studies has shown increased mortality of normal serum T compared with low serum T concentrations. However, two recent retrospective studies reported increased adverse CV events, including mortality, in men who received T prescriptions compared with men who did not.6,7 Those studies have created a firestorm of media attention as well as scrutiny from regulatory bodies regarding the issue of T and CV risk. Despite serious methodological and data management concerns regarding those two studies (see below), their impact on the medical “conversation” regarding T and CV issues has been enormous. It is thus particularly timely, then, to review the literature on this topic so as to provide context and perspective on this important issue. A number of excellent systematic reviews and meta‑analyses of mortality and other CV adverse effects with TTh have been published over the last several years.2,8–10 The purpose of this article is not to repeat those analyses, but rather to review the literature, highlighting notable results and providing an overview of those analyses. Most of these studies investigated overall mortality, whereas others provided specific information on CV mortality. However, it should be noted that overall mortality is often used as a nonspecific surrogate for CV risk since CV disease is the greatest single cause of mortality in industrialized countries.11 TESTOSTERONE AND CARDIOVASCULAR MORTALITY The association of serum T and CV mortality has been extensively studied (Table 1).
Testosterone and CV risk A Morgentaler 27 Table 1: Association between levels of endogenous testosterone and mortality Study
Sub‑fraction Sample size of testosterone used for analysis
Age range/mean Mean Major finding age (year) follow‑up period (year)
Remarks
Haring et al. 201013 CS SHIP
TT
1954
20–79/58.7
7.2
Low TT is associated with increased risk of mortality from all causes and CV disease
HR of low TT for all‑cause mortality: 1.92; 95% CI: 1.18–3.14; P
Open Access
Male Endocrinology
INVITED REVIEW
Testosterone deficiency and cardiovascular mortality Abraham Morgentaler New concerns have been raised regarding cardiovascular (CV) risks with testosterone (T) therapy (TTh). These concerns are based primarily on two widely reported retrospective studies. However, methodological flaws and data errors invalidate both studies as credible evidence of risk. One showed reduced adverse events by half in T‑treated men but reversed this result using an unproven statistical approach. The authors subsequently acknowledged serious data errors including nearly 10% contamination of the dataset by women. The second study mistakenly used the rate of T prescriptions written by healthcare providers to men with recent myocardial infarction (MI) as a proxy for the naturally occurring rate of MI. Numerous studies suggest T is beneficial, including decreased mortality in association with TTh, reduced MI rate with TTh in men with the greatest MI risk prognosis, and reduced CV and overall mortality with higher serum levels of endogenous T. Randomized controlled trials have demonstrated benefits of TTh in men with coronary artery disease and congestive heart failure. Improvement in CV risk factors such as fat mass and glycemic control have been repeatedly demonstrated in T‑deficient men treated with T. The current evidence does not support the belief that TTh is associated with increased CV risk or CV mortality. On the contrary, a wealth of evidence accumulated over several decades suggests that low serum T levels are associated with increased risk and that higher endogenous T, as well as TTh itself, appear to be beneficial for CV mortality and risk. Asian Journal of Andrology (2015) 17, 26–31; doi: 10.4103/1008-682X.143248; published online: 18 November 2014 Keywords: cardiovascular; mortality; myocardial infarction; risk; stroke; testosterone
INTRODUCTION As the use of testosterone (T) therapy (TTh) has increased substantially over the last decade,1 there has been increased attention paid to the health consequences of testosterone deficiency (TD), as well as to the potential risks of its treatment. One of the key topics in this area is the relationship of TD to cardiovascular (CV) health, particularly CV mortality. The purpose of this article is to review the literature regarding this issue. In the 1970s and 1980s, as epidemiologic studies demonstrated that men suffered from higher rates of myocardial infarctions (MIs) and CV deaths than women for every decade of life, it was speculated that T played a significant role in CV disease, as a clear difference between men and women was the presence of substantial serum concentrations of T in men.2 However, this belief largely disappeared once studies investigating the relationship of T and CV disease began to show that atherosclerosis in men was more prevalent in men with low T concentrations, and men with higher T concentrations appeared to be protected.3 Over the last 20 years, the major focus of potential risks of TTh has been its impact on prostate cancer (PCa). Whereas it had been long assumed that raising serum T would increase the risk of PCa and would cause any existing foci of PCa to grow rapidly,4 data accumulated over nearly 20 years failed to support this belief.5 Curiously, just as concerns regarding PCa have declined, we are once again faced with concerns regarding CV risk. As reviewed in greater detail below, a sizable number of observational studies have investigated the association of serum T concentrations and mortality, and more specifically, CV mortality, in Men’s Health Boston, Harvard Medical School, Boston, MA, USA. Correspondence: Dr. A Morgentaler ([email protected]) Received: 05 July 2014; Accepted: 22 July 2014
men. The majority of those studies have shown a significant association between lower serum T concentrations and mortality, with a smaller number showing no association. None of these observational studies has shown increased mortality of normal serum T compared with low serum T concentrations. However, two recent retrospective studies reported increased adverse CV events, including mortality, in men who received T prescriptions compared with men who did not.6,7 Those studies have created a firestorm of media attention as well as scrutiny from regulatory bodies regarding the issue of T and CV risk. Despite serious methodological and data management concerns regarding those two studies (see below), their impact on the medical “conversation” regarding T and CV issues has been enormous. It is thus particularly timely, then, to review the literature on this topic so as to provide context and perspective on this important issue. A number of excellent systematic reviews and meta‑analyses of mortality and other CV adverse effects with TTh have been published over the last several years.2,8–10 The purpose of this article is not to repeat those analyses, but rather to review the literature, highlighting notable results and providing an overview of those analyses. Most of these studies investigated overall mortality, whereas others provided specific information on CV mortality. However, it should be noted that overall mortality is often used as a nonspecific surrogate for CV risk since CV disease is the greatest single cause of mortality in industrialized countries.11 TESTOSTERONE AND CARDIOVASCULAR MORTALITY The association of serum T and CV mortality has been extensively studied (Table 1).
Testosterone and CV risk A Morgentaler 27 Table 1: Association between levels of endogenous testosterone and mortality Study
Sub‑fraction Sample size of testosterone used for analysis
Age range/mean Mean Major finding age (year) follow‑up period (year)
Remarks
Haring et al. 201013 CS SHIP
TT
1954
20–79/58.7
7.2
Low TT is associated with increased risk of mortality from all causes and CV disease
HR of low TT for all‑cause mortality: 1.92; 95% CI: 1.18–3.14; P
